Blockade of CNS dopamine (DA) receptors is the probable mechanism by which neuroleptics exert both their antipsychotic action (APA) and extrapyramidal side effects (EPS). While the anatomic locus of APA is unknown, EPS is probably mediated by the basal ganglia. Clinical tolerance to APA does not occur; yet chronic treatment results in pharmacological and biochemical tolerance in striatal and/or mesolimbic structures; other structures, e.g. cortical and/or amygdaloid, are thus implicated in the APA, since we and others find no biochemical tolerance in some cortical DA areas. In addition, some neuroleptics have a differential capacity to elicit APA and EPS: Clozapine and sulpiride display APA without EPS, while metoclopramide elicits EPS but little APA. Common neuroleptics, such as haloperidol, promote both effects. Systematic dose-response and time-course studies of the effects of acute and chronic treatment with these agents on presynaptic (DOPAC levels, TH activity) and postsynaptic (in vivo cyclic AMP accumulation) parameters in all the above CNS areas are planned. Additional studies, utilizing a similar paradigm, will focus on these dopaminergic parameters during the withdrawal phase following chronic treatment. New insights into the phenomenon of tardive dyskinesia are expected. Significant new data regarding locus and drug specificity for APA and EPS production are expected to aid in the development of new agents and therapeutic strategies for alleviation of psychotic disorders and the attendant side effects of treatment.